Cardiovascular disease is a critical health issue in the US and Western countries. The leading cause of death is heart failure (HF). Almost 5.5 million patients are diagnosed with congestive HF in the U.S and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy for post myocardial infarction (post-MI) HF is extremely important, and the development of a new class of medicine which prevents progression of HF would have a large market opportunity and represent a significant clinical advance. The ultimate goal of this project is to develop a new drug for heart failure (HF) by inhibiting type 5 adenylyl cyclase (AC5). Recently our studies demonstrated that inhibition of AC5 would be a strategy for treating HF. Disruption of AC5 gene in mouse prolongs lifespan by attenuating aging-related HF, protects against HF induced by chronic pressure overload, by excessive sympathetic stimulation and by myocardial ischemia, suggesting that an AC5 inhibitor would be a new class of HF drug. The phase I study will provide definitive evidence that a novel AC5 inhibitor has beneficial effect on post-MI HF in a small animal model. In our preliminary screening for AC5 inhibitors, adenine 9-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(R)), which was used in the clinic for a different indication, showed protection against HF in mice, suggesting a possible clinical utility of AC5 inhibitors for treating HF. In the presen application we will validate the effect of a novel AC5 inhibitor, PMC-6, on post-MI HF by using a mouse HF model. In the Phase II, we will further investigate the effect of PMC-6 on post-MI HF in a large animal model. Additionally, we will develop second generation PMC-6-type drugs with improved potency, better specificity and minimal adverse effects. We will evaluate the pharmacokinetics, drug metabolism, and safety of the most promising second generation AC5 inhibitor to enter into clinical trials. PUBLIC HEALTH RELEVANCE: Almost 5.5 million patients are diagnosed with congestive HF in the U.S and the major cause of HF is myocardial ischemic disease; however, no effective therapy has been established to treat congestive HF. The current investigation is aiming at generating a new class of medicine preventing progression of HF, which should have a large market opportunity and significant clinical importance.